Ma X, Sun J, Papasavvas E, Riemann H, Robertson S, Marshall J, Bailer R T, Moore A, Donnelly R P, Trinchieri G, Montaner L J
The Wistar Institute, Philadelphia, PA 19104, USA.
J Immunol. 2000 Feb 15;164(4):1722-9. doi: 10.4049/jimmunol.164.4.1722.
IL-12 is a pivotal cytokine that links the innate and adaptive immune responses. TNF-alpha also plays a key role in orchestrating inflammation and immunity. The reciprocal influence of these two inflammatory mediators on each other may have significant impact on the cytokine balance that shapes the type and extent of immune responses. To investigate the relationship between TNF-alpha and IL-12 production, we analyzed the effects of exposure of human monocyte-derived macrophages to TNF-alpha on LPS- or Staphylococcus aureus-induced IL-12 production in the presence or absence of IFN-gamma. TNF-alpha is a potent inhibitor of IL-12 p40 and p70 secretion from human macrophages induced by LPS or S. aureus. IL-10 is not responsible for the TNF-alpha-mediated inhibition of IL-12. TNF-alpha selectively inhibits IL-12 p40 steady-state mRNA, but not those of IL-12 p35, IL-1alpha, IL-1beta, or IL-6. Nuclear run-on analysis identified this specific inhibitory effect at the transcriptional level for IL-12 p40 without down-regulation of the IL-12 p35 gene. The major transcriptional factors identified to be involved in the regulation of IL-12 p40 gene expression by LPS and IFN-gamma, i.e., c-Rel, NF-kappaB p50 and p65, IFN regulatory factor-1, and ets-2, were not affected by TNF-alpha when examined by nuclear translocation and DNA binding. These data demonstrate a selective negative regulation on IL-12 by TNF-alpha, identifying a direct negative feedback mechanism for inflammation-induced suppression of IL-12 gene expression.
白细胞介素-12是连接先天性和适应性免疫反应的关键细胞因子。肿瘤坏死因子-α在协调炎症和免疫过程中也发挥着关键作用。这两种炎症介质之间的相互影响可能会对塑造免疫反应类型和程度的细胞因子平衡产生重大影响。为了研究肿瘤坏死因子-α与白细胞介素-12产生之间的关系，我们分析了在存在或不存在干扰素-γ的情况下，人单核细胞衍生的巨噬细胞暴露于肿瘤坏死因子-α对脂多糖或金黄色葡萄球菌诱导的白细胞介素-12产生的影响。肿瘤坏死因子-α是脂多糖或金黄色葡萄球菌诱导的人巨噬细胞分泌白细胞介素-12 p40和p70的有效抑制剂。白细胞介素-10不参与肿瘤坏死因子-α介导的对白细胞介素-12的抑制作用。肿瘤坏死因子-α选择性抑制白细胞介素-12 p40的稳态mRNA，但不抑制白细胞介素-12 p35、白细胞介素-1α、白细胞介素-1β或白细胞介素-6的mRNA。核转录分析确定了这种对白细胞介素-12 p40在转录水平上的特异性抑制作用，而白细胞介素-12 p35基因并未下调。通过核转位和DNA结合检测发现，参与脂多糖和干扰素-γ调节白细胞介素-12 p40基因表达的主要转录因子，即c-Rel、核因子-κB p50和p65、干扰素调节因子-1和ets-2，不受肿瘤坏死因子-α的影响。这些数据证明了肿瘤坏死因子-α对白细胞介素-12的选择性负调节作用，确定了炎症诱导的白细胞介素-12基因表达抑制的直接负反馈机制。
